Esophageal adenocarcinoma arises from precancerous lesion Barrett's metaplasia, in that the process involves discrete genetic mutations and epigenetic changes that are as yet poorly defined. Numerous efforts have been made to identify the genetic mutations associated with cancer. However, most recent finding suggests that the precancerous lesion is initiated from epigenetic abnormalities without genetic mutation. One such epigenetic alteration is change in the modification of histone proteins which package DNA. These epigenetic alterations are found both early and late in tumorigenesis and, in some cases, normal tissues before tumors arise. Our broad hypothesis is that epigenetic alterations resulting from aging as well as environmental and/or dietary factors may predispose an individual to cancer promoting events in esophageal adenocarcinoma. These factors usually do not acquire changes in DNA sequences of our genome. Instead they cause widespread changes in the epigenome, such as modifications on histone proteins. These aberrant histone modifications may alter metabolism or cell growth, which is often associated with different types of cancers. Our preliminary study suggests that changes on histone proteins modification could happen very early in the developing esophageal malignancy and lead to widespread effects on gene expression. Therefore, extending from our initial finding, the immediate goal in this grant proposal is to identify the vulnerable targets under the aberrant histone modifications in both Barrett's metaplasia and esophageal adenocarcinoma. We anticipate that results from our proposed aims will thoroughly dissect the mechanism of cancerous initiation under aberrant epigenome responsible for esophageal cancer. In addition to early detection of Barrett's esophagus and EAC, characterization of epigenetic perturbation could open another avenue to provide direction for novel treatment strategy. The significance of this proposal is that we will identify the vulnerable molecular targets as biomarkers for early detection and also learn the mechanism underlying the development of esophageal cancer in the absence of genetic mutation. Ultimately, our findings could provide direction for novel treatment strategies and/or the prediction of patient therapeutic response.